During FY97 our work exploring the extent to which thermodynamics and kinetics can describe the control of flux in complex systems including glycolysis (J Biol Chem 1994;269: 25502-14) and its interaction with the tricarboxcyclic acid (TCA) cycle, electron transport and oxidative phosphorylation (FASEB J 1995;9:651-8) continued. Most particularly, these studies concentrated upon the limited extent to which alterations in a so-called "rate-limiting" enzyme can alter the overall flux in a metabolic pathway. Rather the control of flux, and with it the control of phenotypic expression, is a result of the kinetic and thermodynamic parameters of each component in the system. It follows from such an analysis that the actions of drugs or hormones cannot be understood simply in terms of changes in one or a combination of "signally pathways." An example of how the complex hormonal signally pathways, initiated by binding of insulin to its receptor, may be duplicated by metabolic substrates was developed (Am J Cardiol 1997;80:50A-64A). Substrate overload is, of course, particularly relevant to alcoholism, where much of the toxicity results from the presence of abnormal levels of normal metabolic substrates. In the coming year, the role of substrate depletion in TCA cycle of brain during alcohol withdrawal will be explored with the aim of finding alternative, non-addictive treatments.